ROLE OF HSP 110 IN TAUOPATHY

HSP 110 在 Tauopathy 中的作用

• 批准号: 8394589
• 负责人: NAHID F MIVECHI
• 金额: --
• 依托单位: CHARLIE NORWOOD VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394589
• 关键词: Acute Brain Injuries; Age; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Appearance; Applications Grants; Axon; Behavioral; Brain; Brain Injuries; Caring; Cause of Death; Cells; Cerebrospinal Fluid; Cessation of life; Clinical; Cognitive; Complex; Development; Disease; Down Syndrome; Event; Exhibits; Exposure to; Family member; Future; Generations; Goals; Heat shock proteins; Impaired cognition; In Vitro; Inherited; Injury; Isomerase; Knowledge; Life; Location; Microtubule-Associated Proteins; Microtubules; Molecular; Molecular Chaperones; Molecular Machines; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Organism; Pathology; Patients; Pattern; Pick Disease of the Brain; Play; Production; Protein Dephosphorylation; Proteins; Records; Recovery; Risk; Role; Senile Plaques; Social Problems; Tauopathies; Testing; Tg2576; Therapeutic; Toxic effect; Traumatic Brain Injury; Variant; Veterans; Wild Type Mouse; age related; amyloid precursor protein processing; brain tissue; combat; corticobasal degeneration; disability; hyperphosphorylated tau; in vivo; mouse model; mutant; pre-clinical; prevent; protein degradation; protein misfolding; response; tau Proteins; tau aggregation

Potential Impact on Veteran's Heath care is that traumatic brain injury (TBI), which is the main cause of death and disability in people under 35 and a common occurrence in combat situations, leads to significant deficiency in cognitive and social problems and significant amyloid beta (A¿) generation. Furthermore, there is evidence of increased amyloid deposition and an increased risk of development of Alzheimer's disease (AD) following TBI. However, our knowledge regarding the treatment of AD is still incomplete. The neuropathological hallmarks of AD and other tauopathies include accumulation of senile plaques and/or neurofibrillary tangles (NFTs) that causes neurons to degenerate. Clinical records suggest that tau, which is localized in axons, plays a pivotal role in neurodegenerative disorders that are related to protein malfunction. Heat shock proteins (Hsps) such as Hsp110 and Hsp70i are highly expressed following exposure to environmental insults. Their role in neuronal disorders is supported by studies showing that several Hsps are components of NFTs. As such, Hsps have been detected in NFTs containing tau, in neuritic plaques of AD brain, and in the brain tissue following TBI. A direct indication of the role of Hsps in neurodegenerative disease is provided by our discovery that hsp110-/- mice exhibit an age-dependent accumulation of hyperphosphorylated tau (p-tau) and neurodegeneration. We have also found that Hsp110, tau, and Pin1 isomerase, whose deletion in mice leads to tauopathy are in the same complexes. Since the Hsp110 family member, Hsp70 has been shown to be involved in amyloid precursor protein (APP) processing in cells, we tested if hsp110-/- mice crossed with mice expressing a mutant APP (Tg2576+) exhibit accelerated pathology in vivo. Results indicate that indeed hsp110- /-Tg2576+ mice exhibit neuritic plaques at a younger age than the hsp110+/+Tg2576+ mice strongly suggesting a role for Hsp110 (and Hsp70i) in AD pathology in vivo. Therefore, understanding the mechanisms by which Hsp110 and Hsp70i prevent p-tau accumulation, reduce AD pathology, and impact TBI are the subject of this grant application. We hypothesize that Hsp110 and Hsp70i are critical for proper dephosphorylation of tau and are protective during AD and following TBI, and prevent neuronal death. In our proposed studies, we will determine the expression and intra-axonal localization of Hsp110, Hsp70i, tau, or if Hsp110 and Hsp70i are substrates of Pin1. As an example of neurodegenerative diseases associated with tauopathy, we will use hsp110-/-Tg2576+ mice to establish the role of Hsp110 complexes in APP processing and A¿ production in vivo; since the expression of Hsps increases following environmental insults and because TBI is known to increase the risk for developing AD, we will investigate if the presence of Hsp110 and Hsp70i play a role in the recovery from TBI, and if transiently increasing the levels of Hsps accelerate recovery following TBI; we will also examine the brain tissue sections from healthy or AD patients to determine the locations of Hsp110, Hsp70i in senile plaques; Finally, we will use cerebral spinal fluid (CSF) from the patients who have received TBI to determine whether the levels of Hsp110 or Hsp70i following injury correlates with the extent of brain injury.

对退伍军人健康护理的潜在影响是创伤性脑损伤 (TBI)，这是死亡的主要原因 35 岁以下人群的残疾以及战斗情况下常见的情况，导致严重缺陷 认知和社会问题以及显着的淀粉样β (A¿) 生成。此外，有证据表明 淀粉样蛋白沉积增加以及患阿尔茨海默病 (AD) 的风险增加 创伤性脑损伤。然而，我们对 AD 治疗的了解仍然不完整。神经病理学 AD 和其他 tau蛋白病的标志包括老年斑和/或神经原纤维缠结的积累 （NFT）导致神经元退化。临床记录表明，位于轴突中的 tau 蛋白发挥着重要作用 在与蛋白质功能障碍相关的神经退行性疾病中发挥着关键作用。热休克蛋白 Hsp110 和 Hsp70i 等 Hsps 在暴露于环境侵害后高度表达。他们的 研究表明，几种 Hsp 是 NFT 的组成部分，这支持了其在神经元疾病中的作用。作为 例如，在含有 tau 的 NFT、AD 大脑的神经炎斑块和脑组织中都检测到了热休克蛋白。 TBI 后。我们的发现直接表明了热休克蛋白在神经退行性疾病中的作用 hsp110-/- 小鼠表现出年龄依赖性的过度磷酸化 tau (p-tau) 积累， 神经变性。我们还发现了 Hsp110、tau 和 Pin1 异构酶，它们在小鼠体内的缺失导致 tau蛋白病处于相同的复合物中。自 Hsp110 家族成员以来，Hsp70 已被证明 参与细胞中淀粉样前体蛋白 (APP) 的加工，我们测试了 hsp110-/- 小鼠是否与小鼠杂交 表达突变 APP (Tg2576+) 表现出体内病理加速。结果表明确实 hsp110- /-Tg2576+ 小鼠比 hsp110+/+Tg2576+ 小鼠更年轻时表现出神经炎斑块，强烈表明 Hsp110（和 Hsp70i）在体内 AD 病理学中的作用。因此，了解其机制 Hsp110 和 Hsp70i 防止 p-tau 积聚、减少 AD 病理并影响 TBI 是本文的主题 拨款申请。我们假设 Hsp110 和 Hsp70i 对于 tau 和 tau 蛋白的正确去磷酸化至关重要 在 AD 期间和 TBI 后具有保护作用，并防止神经元死亡。在我们提出的研究中，我们将 确定 Hsp110、Hsp70i、tau 的表达和轴突内定位，或者 Hsp110 和 Hsp70i 是否 Pin1 的基板。作为与 tau 蛋白病相关的神经退行性疾病的一个例子，我们将使用 hsp110-/-Tg2576+ 小鼠以确定 Hsp110 复合物在体内 APP 加工和 A¿ 产生中的作用； 因为热休克蛋白的表达在环境损害后增加，并且已知 TBI 会增加 发展 AD 的风险，我们将调查 Hsp110 和 Hsp70i 的存在是否在恢复中发挥作用 TBI 后，如果短暂增加热休克蛋白水平可加速 TBI 后的恢复；我们也会 检查健康或 AD 患者的脑组织切片，以确定 Hsp110、Hsp70i 的位置 老年斑；最后，我们将使用来自接受过 TBI 的患者的脑脊液 (CSF) 确定损伤后 Hsp110 或 Hsp70i 的水平是否与脑损伤程度相关。